RESEARCH AND DEVELOPMENT AGREEMENT

 

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                                                                   EXHIBIT 10.16

 

                       RESEARCH AND DEVELOPMENT AGREEMENT

 

                                     BETWEEN

 

                                 SANKYO CO., LTD

 

                                       and

 

                                  ARQULE, INC.

 

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                                                                   EXHIBIT 10.16

 

                                Table of Contents

 

1.       Definitions

         1.1.     "Active Homolog"

         1.2.     "Active ArQule Compound"

         1.3.     "Active Compound"

         1.4.     "Active Sankyo Compound"

         1.5.     "Affiliate"

         1.6.     "Agreement"

         1.7.     "ArQule Compound"

         1.8.     "ArQule Derivative Compound"

         1.9.     "ArQule Patent Rights"

         1,10.    "ArQule Technology"

         1.11.    "Array"

         1.12.    "Base Rate of Interest"

         1.13.    "Chemical Theme"

         1.14.    "Confidential Information"

         1.15.    "Contract Year"

         1.16.    "Derivative Compound"

         1.17.    "Directed Array (tm)"

         1.18.    "Directed Array (tm) Program"

         1.19.    "Disclosing Party"

         1.20.    "Effective Date"

         1.21.    "Extraordinary Expenses"

         1.22.    "FDA"

         1.23.    "Joint Patent Rights"

         1.24.    "Licensed Compound"

         1.25.    "Licensed Compound Set"

         1.26.    "Mapping Array (tm)"

         1.27.    "Mapping Array (tm) Program"

         1.28.    "Net Sales"

         1.29.    "Net Sales Price"

         1.30.    "Party"

         1.31.    "Patent Rights"

         1.32.    "Phase I Clinical Trials"

         1.33.    "Phase II Clinical Trials"

         1.34.    "Phase III Clinical Trials"

         1.35.    "Preclinical Compound"

         1.36.    "Preclinical Development"

         1.37.    "Receiving Party"

         1.38.    "Research Period"

         1.39.    "Research Program"

         1.40.    "Research Plan"

         1.41.    "Royalty-Bearing Product"

         1.42.    "Royalty Period"

 

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                                                                   EXHIBIT 10.16

 

         1.42.    "Sankyo Compound"

         1.44.    "Sankyo Derivative Compound

         1.45.    "Sankyo Patent Rights"

         1.46.    "Steering Committee

         1.47.    "Sublicensee"

         1.48.    "Target"

         1.49.    "U.S. Territory"

         1.50     "Valid Claim"

         1.51     "Worldwide Territory `

 

2.       Management of Research Program

         2.1.     Composition of Steering Committee

         2.2.     Duties of the Steering Committee

         2.3.     Compounds Excluded from the Directed Array (tm) Program

         2.4.     Meetings of the Steering Committee

         2.5.     Cooperation

         2.6.     Visits to Facilities

 

3.       Mapping Array" (tm) Program

         3.1.     Conduct of Mapping Array (tm) Program

         3.2.     Mutual Disclosure

         3.3.     Reservation of Active ArQule Compounds

         3.4.     Mapping Array (tm) Program Payments

         3.5.     Term of Mapping Array (tm) Program

         3.6.     Performance of Mapping Array (tm) Program

 

4.       Directed Array (tm) Program

         4.1.     Description of Directed Array (tm) Program

         4.2.     Conduct of Directed Array (tm) Program

         4.3.     Directed Array (tm) Program Payments

         4.3.1.   Delivery Fee

         4.3.2.   Expenses

         4.4.     Term of Directed Array (tm) Program

 

5.       License Grants: Reversion of Rights

         5.1.     Screening Licenses

         5.2.     Preclinical and Clinical Licenses

         5.3.     Commercialization License

         5.4.     Reversion of Rights: Return of Materials

 

6.       Ownership of Compounds

         6.1.     Sankyo Compounds; Sankyo Derivative Compounds

         6.2.     ArQule Compounds: ArQule Derivative Compounds

 

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                                                                   EXHIBIT 10.16

 

7.       Intellectual Property Rights

         7.1.     Ownership of Patent Rights

         7.2.     Management of Joint Patent Rights

         7.3.     Cooperation of the Parties

         7.4.     Infringement by Third Parties

 

8.       Payments, Reports, and Records

         8.1.     Milestone Payments

         8.2.     Alternative to Milestone Payments

         8.3.     Royalties

         8.4.     Reports and Payments

         8.5.     Invoices: Payments in U.S. Dollars

         8.6.     Payments in Other Currencies

         8.7.     Records

         8.8.     Late Payments

         8,9.     Withholding Tax Payments

               8.9.1. Payments

               8.9.2. Royalty Payments

 

9.       Confidential Information

         9.1.     Definition of Confidential Information

         9.2.     Definition of Confidential Information

         9.3.     Obligations

         9.4.     Exceptions

         9.5.     Return of Confidential Information

         9.6.     Survival of Obligations

 

10.      Representations and Warranties

         10.1.    Authorization

 

11.      Indemnifications and Insurance

         11.1.    Sankyo Indemnity Obligations

         11.2.    Procedure

         11.3.    Insurance

 

12.      Term and Termination

         12.1.    Term

         12.2.    Breach of Payment Obligations

         12.3.    Material Breach

 

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                                                                   EXHIBIT 10.16

 

         12.4.    Effect of Termination

 

13.      Miscellaneous

         13.1     Relationship of Parties

         13.2.    Publicity

         13.3.    Non-Solicitation

         13.4.    Governing Law

         13.5.    Dispute Resolution Procedures

         13.6.    Counterparts

         13.7.    Headings

         13.3.    Binding Effect

         13.9.    Assignment

         13.10.   Notices

         13.11.   Amendment and Waiver

         13.12.   Severability

         13.13.   Entire Agreement

         13.14.   Force Majeure

 

EXHIBIT A

 

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                                                                   EXHIBIT 10.16

 

                       RESEARCH AND DEVELOPMENT AGREEMENT

 

         This Agreement, dated as of November 1, 1997, is between Sankyo Co.,

     LTD ("Sankyo"), a Japanese corporation, having a business address at 5-1,

     Nihonbashi Honcho 3-chome, Chuo-ku Tokyo 103, Japan, and ArQule, Inc.

     ("ArQule"), a Delaware corporation, having a business address at 200 Boston

     Avenue, Medford, Massachusetts, U.S.A.

 

                                    RECITALS

 

         WHEREAS, ArQule has developed certain technology that has applications

     in the discovery and development of pharmaceutical compounds;

 

         WHEREAS, Sankyo desires that ArQule apply its technologies to the

     research and development of pharmaceutical compounds for Sankyo; and

 

         WHEREAS, in exchange for payment by Sankyo of research funds, milestone

     payments and royalties, ArQule is willing to perform certain research and

     development activities for Sankyo, subject to the terms and conditions of

     this Agreement;

 

         NOW, THEREFORE, in consideration of the mutual covenants set forth in

     this Agreement, the Parties hereby agree as follows:

 

1.       Definitions.

 

         1.1.     "Active Homologs" shall mean any ArQule Derivative Compound or

Sankyo Derivative Compound that exhibits substantial homology with an Active

Compound as determined by the Steering Committee.

 

         1.2.     `Active ArQule Compound" shall mean any ArQule Compound or

ArQule Derivative Compound which exhibits confirmed significant functional

activity against a Target. The Steering Committee shall establish the criteria

for "significant functional activity" at the time of selection of each Target.

 

         1.3.     "Active Compound" shall mean any Active ArQule Compound or

Active Sankyo Compound.

 

         1.4.     "Active Sankyo Compound" shall mean any Sankyo Compound or

Sankyo Derivative Compound which exhibits confirmed significant functional

activity against a Target. The Steering Committee shall establish the criteria

for "significant functional activity" at the time of selection of each Target.

 

         1.5.     "Affiliate" shall mean a corporation or other legal entity

that controls, is

 

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                                                                   EXHIBIT 10.16

 

controlled by, or is under common control with such Party. For purposes of this

definition, "control" means the ownership, directly or indirectly, of fifty

percent. (50%) or more of the outstanding equity securities of a corporation

which are entitled to vote in the election of directors or a fifty percent (50%)

or greater interest in the net assets or profits of an entity which is not a

corporation

 

         1.6. "Agreement" shall mean this Research and Development Agreement,

together with Exhibit A hereto.

 

         1.7.    "ArQule Compound" shall mean any organic chemical molecule

that is synthesized by ArQule using its proprietary technology and provided by

ArQule to Sankyo under the Mapping Array (tm) Program.

 

         1.8.     "ArQule Derivative Compound" shall mean a Derivative Compound

synthesized by ArQule from an ArQule Compound under the Directed Array (tm)

Program described in Section 4.

 

         1.9.     "ArQule Patent Rights" shall mean Patent Rights controlled or

owned by ArQule as of the Effective Date or during the Research Period; all to

the extent and only to the extent that ArQule now has or hereafter will have the

right to grant licenses, immunities or other rights thereunder.

 

         1.10.    "ArQule Technology" shall mean all information and data which

is owned by ArQule or licensed by third parties to ArQule prior to or during the

Research Program and is necessary or useful to conduct the screening to discover

Active ArQule Compounds and Active Homologs thereto or to develop, make, use,

sell or seek regulatory approval in any country to market a product containing a

Licensed Compound; all to the extent and only to the extent that ArQule now Las

or hereafter will have the right to grant licenses, immunities or other rights

thereunder.

 

         1.11.    "Array" shall mean a set of samples of structurally related

chemical compounds arranged in a format such as a microtiter screening plate.

 

         1.12.    "Base Rate of Interest" shall mean the base rate of interest

declared from time to time by the Bank of Boston.

 

         1.13.    "Chemical Theme" shall mean the chemical or structural

characteristics shared by a group of compounds as determined by the Steering

Committee pursuant to Section 2,2.

 

         1.14.    "Confidential Information" shall have the meaning set forth in

Section 9.1.

 

         1.15.    "Contract Year" shall mean each twelve (12) month period of

the Research Period, commencing on the Effective Date.

 

         1.16.    "Derivative Compound" shall mean a chemical compound

structurally derived in

 

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                                                                   EXHIBIT 10.16

 

one or more steps from another by a process of modification or partial

substitution of at least one component wherein at least one structural feature

is retained at each process step. The number of intermediate steps or compounds

is not relevant to the classification of a compound as a Derivative Compound. A

compound need not have structural similarity to another compound in order to be

classified as a Derivative Compound.

 

         1.17.    "Directed Array (tm) shall mean an Array comprised of ArQule

Derivative Compounds synthesized by ArQule under the Directed Array (tm) Program

described in Section 4.

 

         1.18.    "Directed Array (tm) Program" shall mean a Directed Array (tm)

Program conducted by ArQule as set forth in Section 4, with each Directed Array

(tm) Program consisting of multiple Arrays derived from one (1) Sankyo Compound

or one (1) Active ArQule Compound.

 

         1.19.    "Disclosing Party" shall mean that Party disclosing

Confidential Information to the other Party under Section 9.

 

         1.20,    "Effective Date" shall mean the first business day of the

month immediately following the date of execution of this Agreement by the

Parties hereto.

 

 

         1.21.    "Extraordinary Expenses" shall mean those expenses incurred

from time to time by ArQule in connection with the Directed Array (tm) Program

which are not (a) direct, out-of-pocket costs provided for in the Research Plan

which are directly attributable to the Directed Array (tm) Program or (b) fixed

overhead costs provided for in the Research Plan which are allocable to the

Directed Array (tm) Program.

 

         1.22.    "FDA" shall mean the United States Food and Drug

Administration (or its foreign equivalent in Japan or Europe).

 

         1.23.    "Joint Patent Rights" shall mean any Patent Rights that are

jointly owned by the Parties, as set forth in Section 7.1(b).

 

         1.24.    "License Compound" shall mean any Active Compound or Active

Homolog thereto with respect to which the Steering Committee has designated in

accordance with Sections 2.2 and 3.2.

 

         1.25.    "Licensed Compound Set" shall mean, with respect to a Licensed

Compound, such Licensed Compound and any Active Homolog thereto.

 

         1.26.    "Mapping Array (tm) " shall mean an Array of ArQule Compounds

synthesized by ArQule under the Mapping Array (tm) Program set forth in

Section 3.

 

         1.27.    "Mapping Array (tm) Program" shall mean the Mapping Array (tm)

component of the Research Program as set forth in Section 3.

 

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                                                                   EXHIBIT 10.16

 

         1.28. "Net Sales" shall mean the aggregate Net Sales Price of

Royalty-Bearing Products in any Royalty Period.

 

         1.29. "Net Sales Price" shall mean the gross amount received on

sales by Sankyo, its Affiliates and Sublicensees of Royalty-Bearing Products,

less the following; (i) trade, quantity, and cash discounts or rebates actually

allowed, (ii) credits or allowances given for rejections or returns, and (iii)

freight, shipping, or other costs of transportation charged to a customer. In

any transfers of Royalty-Bearing Products between Sankyo and an Affiliate, the

Net Sales Price shall be calculated based on the final sale of the

Royalty-Bearing Product to an independent third party. In the event that Sankyo

receives non-monetary consideration for any Royalty-Bearing Products, the Net

Sales Price shall be calculated based on the average price charged by Sankyo for

such Royalty-Bearing Products during the preceding Royalty Period.

 

         1.30.    "Party" means ArQule or Sankyo or their respective Affiliates;

"Parties" means ArQule and Sankyo and theft respective Affiliates,

 

         1.31.    "Patent Rights" shall mean all rights arising under issued

patents and reissues, reexaminations, extensions and supplementary protection

certificates thereof and all patent applications and any divisions,

continuations, or continuations-in-part thereof or patents issuing thereon,

 

         1.32,    "Phase I Clinical Trials" shall mean clinical trials in

healthy adults and/or in a small number of patients commencing upon the filing

of a trial protocol with the appropriate regulatory body and designed to

determine the metabolism and pharmacologic actions of a product in humans, the

side effects associated with increasing doses and to gather evidence on

effectiveness and meeting the requirements established by the FDA or by the

equivalent Japanese agency for Phase I clinical trials, The completion of the

Phase I Clinical Trials will be deemed to have occurred upon the first formal

internal issuance of trial results as measured by trial objectives, or in any

event no later than the commencement of the Phase II Clinical Trials.

 

         1.33.    "Phase II Clinical Trials" shall mean clinical trials in a

small sample of the intended patient population commencing upon the filing of a

trial protocol with the appropriate regulatory body and designed to assess the

efficacy for a specific indication of a compound proposed to be used as a

therapeutic or diagnostic pharmaceutical product, to determine dose tolerance

arid the optimal dose range as well as to gather additional information relating

to safety and potential adverse effects, and meeting the requirements

established by the FDA or the equivalent Japanese agency for Phase H clinical

trials. The completion of the Phase II Clinical Trials will be deemed to have

occurred upon the first formal internal issuance of trial results as measured by

trial objectives, or in any event no later than the commencement of the Phase UI

Clinical Trials.

 

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                                                                   EXHIBIT 10.16

 

         1.34.    "Phase III Clinical Trials" shall mean clinical trials

commencing upon the filing of a trial protocol with the appropriate regulatory

body and designed to demonstrate safety and efficacy of a compound proposed to

be used as a prophylactic, therapeutic or diagnostic pharmaceutical product in

an expanded patient population at geographically dispersed study sites, meeting

the requirements established by the FDA or the equivalent Japanese agency for

Phase In clinical trials. The completion of the Phase Ill Clinical Trials will

be deemed to have occurred upon the first formal internal issuance of trial

results as measured by trial objectives, or in any event no later than the

filing of an NDA.

 

         1.35.    "Preclinical Compound" shall mean any Licensed Compound

selected by Sankyo or an Affiliate of Sankyo to enter into Preclinical

Development.

 

         1.36.    "Preclinical Development" shall mean, with respect to any

Preclinical Compound, the commencement of potency and efficacy testing in animal

models,

 

         1.37.    "Receiving Party" mean that Party receiving Confidential

Information under Section 9.1,

 

         1.38.    "Research Period" shall mean the period during which the

Research Program remains in effect. The duration of the Research Period shall be

a minimum of three (3) years, unless extended by the mutual agreement of the

Parties.

 

         1.39.    "Research Program" shall mean, collectively, each of the

Directed Array (tm) Programs and the Mapping Array (tm) Program.

 

         1.40.    "Research Plan" shall mean a plan of research for the Directed

Array (tm) Program covering a minimum of a six-month period, which shall be

updated quarterly pursuant to Section 2.2 to reflect developments during the

previous three (3) months and extended for the subsequent three (3) months. The

parties will begin development of the initial Research Plan by December 31,

1997. The parties will complete the Research Plan for the first Directed Array

(tm) Program by January 31, 1998 and will complete the Research Plan for the

second Directed Array (tm) Program by March 31, 1998. The completed Research

Plan will be attached to this Agreement as & Exhibit A

 

         1.41.    "Royalty Bearing Product" shall mean a product containing as

one of its constituents (a) any Active ArQule Compound; (b) any ArQule

Derivative Compound; (c) any Sankyo Derivative Compound; or (d) any other

Derivative Compound discovered or designed by Sankyo from any ArQule Compound,

ArQule Derivative Compound or Sankyo Derivative Compound, or otherwise as a

result of information provided by ArQule to Sankyo under the Mapping Array (tm)

Program described in Section 3, or the Directed Array (tm) Program described in

Section 4 developed.

 

         1.42.    "Royalty Period" shall mean, with respect to each

Royalty-Bearing Product, every calendar quarter, or partial calendar quarter,

commencing with the first commercial sale of

 

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                                                                   EXHIBIT 10.16

 

such Royalty-Bearing Product in any country and ending on the later to occur of

(i) the end of the quarter during which all Valid Claims of all Patent Rights

covering such Royalty-Bearing Product expire in the applicable country, or (ii)

ten (10) years after such first commercial sale in the applicable country.

 

         1.43.    "Sankyo Compound" shall mean any chemical compound provided by

Sankyo or its Affiliates to ArQule under the Directed Array (tm) Program

described in Section 4.

 

         1.44.    "Sankyo Derivative Compound" shall mean a Derivative Compound

synthesized by ArQule from a Sankyo Compound under the Directed Array (tm)

Program describe in Section 4.

 

         1.45.    "Sankyo Patent Rights" shall mean Patent Rights controlled or

owned by Sankyo as of the Effective Date or during the Research Period; all to

the extent and only to the extent that Sankyo now has or hereafter will have the

right to grant licenses, immunities or other rights thereunder.

 

         1.46,    "Steering Committee" shall have the meaning set forth in

Section 2.1.

 

         1.47.    "Sublicensee" shall mean any non-Affiliate third party

licensed by Sankyo to make, use (except where the right to use accompanies the

sale of any Royalty-Bearing Product by Sankyo or its Affiliates or Sublicensees)

or sell any Royalty-Bearing Product.

 

         1.48.    "Target" shall mean any biological target selected by

Sankyo for which Sankyo has certain proprietary technology and/or expertise.

 

         1.49.    "U.S. Territory" shall mean the fifty states comprising the

United States of America and all American possessions.

 

         1.50.    "Valid Claim" shall mean either (a) a claim of an issued

patent that has not been held unenforceable or invalid by an agency or a court

of competent jurisdiction in any unappealable or unappealed decision or (b) a

claim of a pending patent application that has not been abandoned or finally

rejected without the possibility of appeal or refiling.

 

         1.51.    "Worldwide Territory" shall mean the world excluding the U.S.

Territory.

 

         1.52.    The above definitions are intended to encompass the defined

terms in both the singular and plural tenses.

 

2.       Management of Research Program,

 

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                                                                   EXHIBIT 10.16

 

         2.1.     Composition of Steering Committee. The Parties hereby

establish a Steering Committee comprised of six (6) members, with three (3)

representatives appointed by each Party. The initial members of the Steering

Committee shall be as follows:

 

                                                  Sankyo Representative

 

               Douglas Burdi, Ph.D.

 

               Dayid L Coffen, Ph.D.

 

               Kaplan, Ph.D.

 

A Party may change one or more of its representatives to the Steering Committee

at any time upon notice to the other Party. Each Party will designate one of its

representatives as its team leader.

 

         2.2.     Duties of the Steering Committee. The Steering Committee shall

direct and administer the Research Program. With respect to each Directed Array

(tm) Program, the Steering Committee shall specifically determine the following:

(i) the appropriate objectives of each Chemical Theme and/or Active Compound to

be submitted to the Directed Array (tm) Program; (ii) the appropriate number and

type of Chemical Themes to be submitted to the Directed Array (tm) Program,

subject to ArQule's right to exclude certain compounds as set forth in Section

2.3 below; (iii) the appropriate number of compounds that ArQule should generate

in a Directed Array (tm) for a particular Chemical Theme; and (iv) the

appropriate amount of each compound in a Directed Array (tm) that ArQule should

deliver to Sankyo for further research and development. The scope of each

Chemical Theme will be determined on the basis of the following criteria: (i)

the specific reaction or reaction sequence used to combine members of two or

more discrete chemical units in which each chemical unit bears the functional

group(s) required for the specific reaction(s) that result in the combination of

the chemical units; and (ii) the extent to which a class of compounds is related

by a recurring structural motif associated with a particular biological

activity. In addition, the Steering Committee shall (i) determine whether any

Active Compound should be designated as a Licensed Compound; (ii) determine and

update the list of Licensed Compounds; (iii) determine the allocation of the

funding and personnel resources to be contributed by ArQule under this

Agreement; (iv) revise and extend the Research Plan each calendar quarter for

the subsequent six (6) months based on prior developments; and (v) resolve

matters involving scientific questions.

 

         2.3.     Compounds Excluded from the Directed Array (tm) Program.

ArQule shall have the right, at the time Sankyo seeks to include any Active

ArQule Compound or Active Homolog thereto in any Directed Array (tm) Program, to

exclude from such Directed Array (tm) Program any Active ArQule Compound or

Active Homolog thereto that is at that time either (I) included within a

Directed Array (tm) Program for a third party(1) (ii) being optimized by a third

party from a Mapping Array (tm) Program, (iii) previously licensed or reserved

by a third party, or (iv) is

 

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                                                                   EXHIBIT 10.16

 

included within an existing ArQule internal development program.

 

         2.4.     Meetings of the Steering Committee. The Steering Committee

shall communicate regularly, but in no event less than monthly, via written

project status reports through written communications means, including, without

limitation, electronic mail. A member of the committee from each Party will

promptly respond to such communications where appropriate within seven (7) days

of its receipt by such member, In the event that questions or issues arise from

such written communications that cannot be, or are not being effectively

addressed by such written communications, or upon request by any member of the

Steering Committee, the Steering Committee shall promptly conduct one or more

telephone conferences to address such questions or issues and shall prepare and

deliver to each Party a brief written report describing the significant issues

and discussions that take place during such telephone conference(s). A

representative of the Steering Committee jointly appointed by its members shall

provide each member with five (5) business days notice of the time of any such

telephone conferences and the proposed agenda with respect thereto, unless

waived by all members. The Steering Committee shall meet at least once each

quarter at the facilities of ArQule, or at such other times and locations as the

Steering Committee determines. A representative of the Steering Committee

jointly appointed by its members shall provide each member with five (5)

business days notice of the time and location of meetings, unless such notice is

waived by all members. If a designated representative of a Party cannot attend

any meeting of the Steering Committee, such Party may designate a different

representative for that meeting without notice to the other Party, and the

substitute member will have full power to vote on behalf of the permanent

member. Except as otherwise provided in this Section 2, all actions and

decisions of the Steering Committee will require the unanimous consent of all of

its members. If the Steering Committee fails to reach agreement upon any matter,

the dispute will be resolved in accordance with the procedures set forth in

Section 13.5 below. Within ten (10) days following each quarterly meeting of the

Steering Committee, the Steering Committee shall prepare and deliver, to both

Parties, a written report describing the decisions made, conclusions and actions

agreed upon.

 

         2.5.     Cooperation. Each Party agrees to provide the Steering

Committee with information and documentation as reasonably required for the

Steering Committee to fulfill its duties under this Agreement. In addition, each

Party agrees to make available its employees and consultants as reasonably

requested by the Steering Committee, The Parties anticipate that members of the

Steering Committee will communicate informally with each other and with

employees and consultants of the Parties on matters relating to the Directed

Array (tm) Program.

 

         2.6.     Visits to Facilities. Members of the Steering Committee shall

have reasonable access to the facilities of each Party where activities under

this Agreement are in progress, but only during normal business hours and with

reasonable prior notice. Each Party shall bear its own expenses in connection

with such site visits.

 

3.       Mapping Array (tm) Program.

 

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                                                                   EXHIB